Structural insights into the regulation of NADPH binding to reductase domains of nonribosomal peptide synthetases: A concerted loop movement model

Kinatukara, Priyadarshan; Patel, Ketan D.; Haque, Asfarul S.; Singh, R. P.; Gokhale, Rajesh S.; Sankaranarayanan, Rajan

doi:10.1016/j.jsb.2016.03.014

Cited by 9 publications

(16 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An additional study by the same group illuminated a “concerted loop movement model” cofactor binding mechanism mediated by intermodular communication between the TR domain and the preceding T domain, which distinguishes TR domains from the canonical single domain SDR family of enzymes. 23 In this model, the absence of a fully mature product at the T domain limits flexible gating and catalytic loop motifs of the reductase domain to sampling of conformations that prevent compatibility with NADPH binding. Only upon formation of a fully mature product on the 4’-Ppant arm of the T domain does a re-orientation of the covalent T-TR linker region occur that triggers a coordinated transition of the gating and catalytic loops from the apo to the NADPH-bound state.…”

Section: Thioester Reductase Domainsmentioning

confidence: 99%

“…This GPL thioester reductase domain has received considerable structural and mechanistic characterization as summarized in Section 2.2 and maintains an overall homology of 45–50% with reductase domains that reduce the thioester to an aldehyde or an alcohol or catalyze a Dieckmann cyclization (Section 11). 22, 23…”

Section: Primary Alcohol-containing Natural Productsmentioning

confidence: 99%

See 1 more Smart Citation

Natural products from thioester reductase containing biosynthetic pathways

et al. 2018

View full text Add to dashboard Cite

Thioester reductase domains catalyze two- and four-electron reductions to release natural products following assembly on nonribosomal peptide synthetases, polyketide synthases, and their hybrid biosynthetic complexes. This reductive off-loading of a natural product yields an aldehyde or alcohol, can initiate the formation of a macrocyclic imine, and contributes to important intermediates in a variety of biosyntheses, including those for polyketide alkaloids and pyrrolobenzodiazepines. Compounds that arise from reductase-terminated biosynthetic gene clusters are often reactive and exhibit biological activity. Biomedically important examples include the cancer therapeutic Yondelis (ecteinascidin 743), peptide aldehydes that inspired the first therapeutic proteasome inhibitor bortezomib, and numerous synthetic derivatives and antibody drug conjugates of the pyrrolobenzodiazepines. Recent advances in microbial genomics, metabolomics, bioinformatics, and reactivity-based labeling have facilitated the detection of these compounds for targeted isolation. Herein, we summarize known natural products arising from this important category, highlighting their occurrence in Nature, biosyntheses, biological activities, and the technologies used for their detection and identification. Additionally, we review publicly available genomic data to highlight the remaining potential for novel reductively tailored compounds and drug leads from microorganisms. This thorough retrospecive highlights various molecularfamilies with especially privileged bioactivity while illuminating challenges and prospects toward accelerating the discovery of new, high value natural products.

show abstract

Section: Thioester Reductase Domainsmentioning

confidence: 99%

Section: Primary Alcohol-containing Natural Productsmentioning

confidence: 99%

Natural products from thioester reductase containing biosynthetic pathways

et al. 2018

View full text Add to dashboard Cite

show abstract

“…27, 36 Additionally, some NRPS proteins terminate not in a thioesterase domain but rather in a reductase domain that catalyzes the NADPH dependent formation of a terminal aldehyde that itself may be subject to further spontaneous or enzyme catalyzed modification. 37, 38 …”

Section: The Biochemistry and Structural Biology Of The Nonribosommentioning

confidence: 99%

“…In addition to the carrier protein and the core condensation and adenylation domains, structures exist for the additional NRPS domains, including the chain terminating thioester 72, 73 and reductase 37, 38, 74, 75 domains, as well as the initiating formyltransferase domain (Fig. 1D).…”

Section: The Biochemistry and Structural Biology Of The Nonribosommentioning

confidence: 99%

Nonribosomal peptide synthetase biosynthetic clusters of ESKAPE pathogens

Gulick

2017

Nat. Prod. Rep.

View full text Add to dashboard Cite

Overview Natural products are important secondary metabolites produced by bacterial and fungal species that play important roles in cellular growth and signaling, nutrient acquisition, intra- and interspecies communication, and virulence. A subset of natural products is produced by nonribosomal peptide synthetases (NRPSs), a family of large, modular enzymes that function in an assembly line fashion. Because of the pharmaceutical activity of many NRPS products, much effort has gone into the exploration of their biosynthetic pathways and the diverse products they make. Many interesting NRPS pathways have been identified and characterized from both terrestrial and marine bacterial sources. Recently, several NRPS pathways in human commensal bacterial species have been identified that produce molecules with antibiotic activity, suggesting another source of interesting NRPS pathways may be the commensal and pathogenic bacteria that live on the human body. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) have been identified as a significant cause of human bacterial infections that are frequently multidrug resistant. The emerging resistance profile of these organisms has prompted calls from multiple international agencies to identify novel antibacterial targets and develop new approaches to treat infections from ESKAPE pathogens. Each of these species contains several NRPS biosynthetic gene clusters. While some have been well characterized and produce known natural products with important biological roles in microbial physiology, others have yet to be investigated. This review catalogs the NRPS pathways of ESKAPE pathogens. The exploration of novel NRPS products may lead to a better understanding of the chemical communication used by human pathogens and potentially to the discovery of novel therapeutic approaches.

show abstract

“…As the PCP domain is positioned immediately downstream of the adenylation domain, this change of orientation of the C-terminal subdomain influences the location of the PCP domain and, as described below, is a critical feature to shuffle the peptide intermediates between catalytic domains. Finally, structures of the terminal thioesterase [26,27] or reductase [28–30] domains demonstrate that these enzymes belong to larger families of enzymes that catalyze similar chemistry.…”

Section: Combining Nrps Domains To Build a Modulementioning

confidence: 99%

Structural insight into the necessary conformational changes of modular nonribosomal peptide synthetases

Gulick

2016

Current Opinion in Chemical Biology

View full text Add to dashboard Cite

Nonribosomal peptide synthetases (NRPSs) catalyze the assembly line biosynthesis of peptide natural products that play important roles in microbial signaling and communication. These multidomain enzymes use an integrated carrier protein that delivers the growing peptide to the catalytic domains, requiring coordinated conformational changes that allow the proper sequence of synthetic steps. Recent structural studies of NRPSs have described important conformational states and illustrate the critical role of a small subdomain within the adenylation domains. This subdomain alternates between catalytic conformations and also serves as a linker domain, providing further conformational flexibility to enable the carrier to project from the core of NRPS. These studies are described along with remaining questions in the study of the structural dynamics of NRPSs.

show abstract

Structural insights into the regulation of NADPH binding to reductase domains of nonribosomal peptide synthetases: A concerted loop movement model

Cited by 9 publications

References 27 publications

Natural products from thioester reductase containing biosynthetic pathways

Natural products from thioester reductase containing biosynthetic pathways

Nonribosomal peptide synthetase biosynthetic clusters of ESKAPE pathogens

Structural insight into the necessary conformational changes of modular nonribosomal peptide synthetases

Contact Info

Product

Resources

About